I am an Assistant Professor of Medicine at Johns Hopkins University Division of Cardiology in my second year as faculty. I have always been interested in basic science research, linking this into a career in academic cardiology. I believe that funding through the NIH Mentored Clinical Scientist Development Award will be instrumental to achieving success as a physician scientist. My short-term career objectives are to expand my skills and knowledge base sufficiently over the next five years to make a smooth transition to independent investigator. My long-term goal is to translate basic scientific discoveries into new approaches to treat and prevent heart failure, and to become a leader in translational cardiovascular research, with specific focus in cardiac hypertrophy and heart failure. Research my prior efforts have identified a critical role for thrombospondin-4 (TSP4) in cardiac adaptation to loading conditions. In this proposal I aim to test the general hypothesis that TSP4 is a critical stress biosensor that mediates cardiac adaptation to pressure through stretch-mediated calcium activation. Using different mouse models, I will integrate molecular gain and loss of function approaches as well as state-of-the art in vivo and in vitro techniques to test each specific aim proposed. I will establish a definite link between TSP4 and stretch-mediated cardiac myocyte increases in calcium, augmented sensitivity of contractile proteins to calcium or both;and determine the source of calcium affected by the lack of TSP4. I will also test whether upregulation of TSP4 is protective to the heart when exposed to high pressure, preventing its transition to heart failure. the environment. The research environment provided by johns Hopkins University as well as the mentors and collaborators outlined in this application will assist in a successful completion of the candidate's career and research goals. The Division of Cardiology and johns Hopkins University have a long history of training successful basic researchers in a supportive and collaborative environment. We have assembled a team of established faculty with many years of productive research experience and tremendous prior mentoring experience. Combining the experience of Dr. David Kass (Johns Hopkins University) and Dr. Jonathan Lederer (University of Maryland) will be key to the success of this proposal. Each has distinct, complementary strengths in areas of research relevant to this proposal. In addition both members of the mentoring committee serve as excellent role models for the applicant's career development into an independent investigator. PUBLIC HEALTH RELEVANCE: Heart failure currently affects >5 million individuals in the United States, with an estimated doubling of that population by 2037. This proposal seeks to identify the cellular mechanisms through which thrombospondin-4, an extracellular matrix glycoprotein found in the heart, interacts with cardiac myocytes protecting them from pressure-load stress, thus preventing the transition to heart failure. This can lead to future novel therapies aimed to prevent and/or cure this disease.